We have examined the thermodynamics of protein self-association, protein-ligand binding and protein-nucleic acid interactions and interpreted these with reference to the known thermochemistry of non-covalent interactions of small molecules. We find that: 1) although there is variation in the magnitudes and signs of the enthalpy and entropy changes accompanying these associations, the widespread occurrence of negative enthalpy and entropy changes for self-association and ligand-binding of globular proteins can only be accounted for on the basis of hydrogen-binding and non-covalent van der Waals' interactions taking place in an environment of low dielectric constant; 2) positive entropy changes arise from solvent molecules liberated upon association or from ionic and salt-bridge types of interactions; 3) the signs and magnitudes of the enthalpy and entropy changes results from the relative extent of the interactions described in (1) and (2). We have proposed a two-stage conceptual model for association processes based upon these two classes of interaction effects that provides a qualitative understanding of the thermodynamics of protein association processes.